Phenylimidazolines for producing a neuronal blocking and antihypertensive effect

ABSTRACT

The novel compounds of this invention are of the imidazoline class of heterocycles having substituents in the 2 and 4 imidazoline ring positions and optionally in the 3-position. Substituents in the 2-position include amino, hydroxyamino, alkylamino, benzylamino, halobenzylamino, dihalobenzylamino, allylamino, cycloalkylamino, hydrazino, and alkylidenehydrazino. Optional 3-position substituents are alkyl and benzyl. The substituent in the 4-position is comprised of phenyl or R-phenyl in which the R-substituent is selected from halogen, alkyl, benzyloxy, alkoxy, dialkoxy, 3-hydroxy, 3,4-dihydroxy, trifluoromethyl, phenyl, halophenyl, or alkylphenyl. The novel imidazolines have antihypertensive and neuronal blocking properties. They are prepared by cyclization of appropriately substituted 1-phenylethylenediamines with cyanogen bromide or by displacement of a methylmercapto grouping from an appropriately substituted 2-methylthioimidazoline. Representative embodiments of this invention are 2-amino-4-(4-chlorophenyl)-2-imidazoline and 2-amino-4-(3,4-dichlorophenyl)-2-imidazoline.

United States atent [191 Matier et al.

[ Aug. 5, 1975 PHENYLIMIDAZOLINES FOR PRODUCING A NEURONAL BLOCKING AND ANTII-IYPERTENSIVE EFFECT [75] Inventors: William Lesley Matier; William Timmey Comer, both of Evansville, Ind.

[73] Assignee: Mead Johnson & Company,

Evansville, Ind.

[22] Filed: June 10, 1974 21 Appl.No.:477,7l8

Related U.S. Application Data [60] Division of Ser. No. 268,380, July 3, 1972, Pat. No. 3,821,244, which is a continuation-in-part of Ser. No. 172,321, Aug. 16, 1971, abandoned.

[52] U.S. Cl 424/273; 424/273 [51] Int. Cl. A61K 27/00 [58] Field of Search 424/273 [56] References Cited Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Robert H. Uloth; Robert E. Carnahan 5 7] ABSTRACT The novel compounds of this invention are of the imidazoline class of heterocycles having substituents in the 2 and 4 imidazoline ring positions and optionally in the 3-position. Substituents in the 2-position include amino, hydroxyamino, alkylamino, benzylamino, halobenzylamino, dihalobenzylamino, allylamino, cycloalkylamino, hydrazino, and alkylidenehydrazino. Optional 3-position substituents are alkyl and benzyl. The substituent in the 4-position is comprised of phenyl or R-phenyl in which the R-substituent is selected from halogen, alkyl, benzyloxy, alkoxy, dialkoxy, 3- hydroxy, 3,4-dihydroxy, trifluoromethy], phenyl, halophenyl, or alkylphenyl. The novel imidazolines have antihypertensive and neuronal blocking properties. They are prepared by cyclization of appropriately substituted l-phenylethylenediamines with cyanogen bromide or by displacement of a methylmercapto grouping from an appropriately substituted 2- methylthioimidazoline. Representative embodiments of this invention are 2-amino-4-(4-chlorophenyl)-2- imidazoline and 2-amino-4-(3,4-dichlorophenyl)-2- imidazoline.

23 Claims, N0 Drawings 1 PHENYLIMIDAZOLINES FOR PRODUCING A NEURONAL BLOCKING AND ANTIHYPERTENSIVE EFFECT CROSS-REFERENCE TO RELATED APPLICATIONS This application is a division of copending US. Ser. No. 268,380 filed July 3, 1972 and now US. Pat. No. 3,821,244, patented June 28, 1974 which in turn is a continuation-in-part application of then copending U.S. Ser. No. 172,321 filed Aug. 16, 1971, now abandoned.

BACKGROUND OF THE INVENTION The present invention is concerned with substituted imidazolinesand acid addition salts thereof. This invention relates to novel imidazolines displaying a useful range of biological properties. They are, specifically, neuronal blocking and/or antihypertensive agents. Neuronal blocking agents are capable of producing a pharmacological effect similar in many respects to a sympathectomy. Such agents are of interest in experimental biology, comparative pharmacology, and in the treatment of hypertension. For example, guanethidine, a neuronal blocking agent structurally unrelated to the imidazolines of the present invention, is a therapeutically effective antihypertensive agent.

The imidazolines of this invention bear a structural resemblance to 2-amino-4-phenyl-2-imidazoline which is a prior art imidazoline reported to be a ganglionic stimulant described by H. Wollweber, et al., Med. Chem., Abhandl. Med. Chem. Forschungstatten Farbwerke Hoechst A.G., 7, 256 (1963), CA 61:652f (1964). As an antihypertensive and a neuronal blocking agent, we have found 2-amino-4-phenyl-2- imidazoline to be essentially inactive, whereas the novel imidazolines claimed herein have significant antihypertensive and/or neuronal blocking activity.

SUMMARY OF THE INVENTION This invention relates generally to a series of novel imidazolines. More particularly, it relates to imidazolines having substitutents in the 2, 4, and optionally in the 3 positions of the imidazoline ring and to the nontoxic pharmaceutically acceptable acid addition salts thereof. The imidazolines of this invention possess valuable pharmacological properties, including neuro nal blocking activity, which render them useful as antihypertensive agents. This invention is further concerned with a therapeutic process for producing a neuronal blocking effect in mammals comprising the administration of the imidazolines of the present invention thereto.

The novel imidazolines of the present invention are comprised of imidazolines which have substituents in the 2, 3, and 4 positions represented A, B, and Y radicals respectively.

Radical B in the 3-position represents hydrogen, lower alkyl and benzyl groupings.

Radical Y in the 4-position is selected from the group consisting of phenyl and an R-phenyl radical of the formula:

When Y is the phenyl radical, A is selected from a group consisting of benzylamino, halobenzylamino, e.g., 4-chlorobenzylamino, 2-chlorobenzylamino, 2,6- dichlorobenzylamino, 3,4-.dichlorobenzylamino; and 3-dimethylaminopropylamino.

When Y is the R-phenyl radical, R is halogen, e.g., chlorine, fluorine, bromine and iodine; lower alkyl, benzyloxy, lower alkoxy, lower dialkoxy, 3-hydroxy, 3,4-dihydroxy, trifluoromethyl, phenyl, 4-halophenyl, and 4-(lower alkyl)phenyl. When R is selected from the group consisting of halogen and lower alkyl, the phenyl ring can optionally have up to 2 additional substituents which are independently selected from halogen and lower alkyl.

Radical A in the 2 position when Y is R-phenyl represents a member of the group consisting of amino, hydroxyamino, lower alkylamino, benzylamino, halobenzylamino, dihalobenzylamino, allylamino, cycloalkylamino from 3 to 6 carbon atoms inclusive, e.g., cyclopropyla rnino, cyclobutylamino, cyclopentylamino, cyclohexylamino; hydrazino, halobenzylidenehydrazino, e.g., 4-chlorobenzylidenehydrazino, 2- chlorobenzylidenehydrazino; dihalobenzylidenehydrazino, e.g., 3,4-dichlorobenzylidenehydrazino, 2,6- dichlorobenzylidenehydrazino; and alkylidenehydrazino.

It is to be understood that by the term lower alkyl and lower alkoxy as used herein, it is meant that the carbon chains which comprise these groups include both straight and branched chain carbon radicals of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain radicals are methyl, ethyl, propyl, isopropyl, 1- butyl, l-methylpropyl, 2-methylpropyl, and tert.-butyl.

By the term independently selected as used herein it is meant that the halogen or lower alkyl substituents may or may not be identical when the R group in the phenyl radical consists of halogen and lower alkyl.

By the term alkylidene, as utilized herein, it is intended to refer to carbon chains of from 2 to 6 carbon atoms inclusive which are double-bonded through a single carbon atom thereof, to the hydrazine group.

- They are derived from alkyl aldehydes such as acetaldehyde, propionaldehyde, bu't'yraldehyde, isobutyraldehyde, hexaldehyde and the like, or alkanones such as acetone, methylethylke'tone, diethylketone, 2- heptanone and the like. Exemplary of suitable alkylidene radicals are illustratively represented by the formula:

cH (cH cH=, CHSCHZQ: (cn cn c=,

3 lactic, succinic, maleic, mucic, tartaric, citric, gluconic, benzoic, cinnamic, isethionic, fumaric, and related acids.

As will be clear to those skilled in the art, the subject imidazolines and their salts can exist in more than one tautomeric modification as illustrated by structures 1-5 which depict various positional tautomers of Z-amino- 4-(4-chlorophenyl)imidazoline and 2-amino-3-benzyl- 4-(4-chlorophenyl) imidazoline bases.

W CH C l-I N4:... (5) CHZCSHS Without being bound by any theory, we believe that protonated imidazolines, as is the case with the acid addition salts, are best represented by a delocalized double bond rather than fixed double bonds as shown in the above tautomeric forms. Illustrating a delocalized double bond is structure 6 which represents a salt of 2- amino-4-(4-chlorophenyl)-2-imidazoline in which X symbolizes an anion.

Evidence thatdouble bonds in the subject imidazolines are delocalized rather than fixed is provided by infrared spectra which clearly show strong NI-I absorption in the free amino region (3,1'00-3,400 Cmf) rather than in the ammonium region and strong C=N absorption at 1,685 Cm.- which is characteristic of a disubstituted guanidinium.

The novel imidazolines which are the subject of the present invention can be depicted according to Formulas I and II wherein the symbol B has the meaning defined above. Dotted lines which extend from ring position 2 represent a delocalized bond which is intended to represent the interchangeable tautomeric forms of the novel imidazolines illustrated by structures 1-5.

Formula I R5 R B Formula II In Formula I, R can be hydrogen in which case the symbol A signifies a member of the group consisting of benzylamino, halobenzylamino and 3- dimethylaminopropylamino.

In Formula I, R? can also signify a halogen, lower alkyl, benzyloxy, lower alkoxy, lower dialkoxy, 3- hydroxy, 3,4-dihydroxy, trifluoromethyl, phenyl, 4- halophenyl, and 4-(lower alkyl)phenyl. Whenever R is as described above, by excluding hydrogen, A signifies a member of the group consisting of amino, hydroxyamino, lower alkylamino, benzylamino, halobenzylamino, dihalobenzylamino allylamino, cycloalkylamino, hydrazino, halobenzylidenehydrazino, dihalobenzylidinehydrazino, and alkylidenehydrazino. In Formula II, R signifies halogen or lower alkyl and R and R signify independently selected halogen or lower alkyl; and A is as above when R excludes hydrogen. By halo and halogen it is intended to include four halogens.

It will be readily apparent to those skilled in the art that compounds of the present invention exist as stereoisomers inasmuch as position 4 of the imidazoline ring contains an asymmetric carbon atom and it is to be understood that all stereoisomeric forms of the substances of Formulas I and II are included within the scope of the present invention. Racemic modifications of the imidazolines can be resolved into optical antipodes according to procedures known to the art such as, by reaction with optically-active acids to provide diastereoisomeric salts. Separation of these salts according to physico-chemical properties and liberation of the optically active bases from the salts.

An alternate and preferred method providing the optical antipodes of the substances of this invention is to employ optically pure l-phenylethylenediamines. These amines can be cyclized to the optically active imidazolines of the present invention according to methods hereinafter described.

A preferred process for preparing novel imidazolines of the present invention wherein the A radical is limited to amino is represented by the following reaction scheme in which R and B have the same meaning given above.

CNBre.

phenylethylenediamine and cyanogen bromide are contacted and mixed in an inert organic solvent as a re-, action medium. Benzene ,is a preferred solvent for the cyclization but other solvents may also be employed, such as, ether, toluene, acetonitrile, chloroform, and

the like. Preferably, the reaction is conducted at a temperature of about 25C. and is complete in from about 0.5 hr. to 16 hr. Reaction temperatures appreciably below room temperature can be used but their use may extend the reaction time. Similarly, reaction temperatures-higher than 25C. can be employed with a concomitant decrease in reaction time.

After the reaction is complete, the product is obtained by conventional methods, for example by filtration and crystallization from a suitable solvent, such as alkanols, water, alkanones, and ethers.

Displacement of the 2-methylthio functionality of 2- methylthioimidazolines according the following reaction scheme provides imidazolines wherein the symbols B, Y, and A are as defined above.

NH N-H Y 4 Y 4*,

A B B Formula V Formula VI Novel imidazolines wherein the A radical in the 2 position is an alkylidenehydrazino or halobenzylidenehydrazino substituent are produced from the corresponding 2-hydrazinoimidazolines by conventional procedures for the preparation of hydrazones. For example,

condensation of the appropriate 2- hydrazinoimidazoline with an alkyl aldehyde, alkanone, or halobenzaldehyde in an inert solvent with a catalytic amount of acid and the elimination of water provides 2-alkylidenehydrazinoimidazolines and 2- (halobenzylidenehydrazino)imidazolines of the present invention.

The l-phenylethylenediamine intermediates which are used as starting materials for the preparation of the imidazolines of the present invention are obtained by methods in themselves well known; refer to Wagner 6 and Zook, Synthetic Organic Chemistry (Wiley) pages 605, 606, 658; L. E. Kholodov, et al., J. Org. Chem. USSR, 1, 2103 1965); and Ruggen, et al., Gazz. Chim, ltal., 54, 554 (1924).

A preferred method comprises cyanoammonolysis of the corresponding substituted benzaldehyde according to the Strecker synthesis to provide oz-aminophenylacetonitriles or a-benzylaminophenylacetonitriles which are then reduced by catalytic or chemical means to the 1-phenylethylenediamines.

Some of the substituted benzaldehydes which may be used are:

4-chlorobenzaldehyde,

2-chlorobenzaldehyde,

4-bromobenzaldehyde,

2,4-dichlorobenzaldehyde,

2,6-dichlorobenzaldehyde,

3,4-dichlorobenzaldehyde, 2,4-dibromobenzaldehyde,

4-methylbenzaldehyde,

4-ethylbenzaldehyde,

4-propylbenzaldehyde,

4-isopropylbenzaldehyde,

4-butylbenzaldehyde,

4-tert.-butylbenzaldehyde,

4-fluorobenzaldehyde,

4-trifluoromethylbenzaldehyde,

3-trifluoromethylbenzaldehyde, 4-methoxybenzaldehyde,

3-methoxybenzaldehyde,

3-benzyloxybenzaldehyde,

3,4-dimethoxybenzaldehyde,

3,4-dibenzyloxybenzaldehyde, and the like.

Reduction of a-aminonitriles such as a-amino-2,6- dichlorophenylacetonitrile is carried out with diborane or lithium aluminum hydride in an inert solvent, e.g., tetrahydrofuran or ether. With a-benzylaminophenylacetonitriles, the preferred route is first reduction with lithium aluminum hydride in ether at 0C. to a B-benzylaminophenethylamine which is then debenzylated catalytically employing palladium on carbon catalyst, or cyclized with cyanogen bromide as described above. I

The imidazolines of the present invention have valuable neuronal blocking properties and thus are particularly useful in experimental and comparative pharmacology and in treating conditions in mammals responsive to administration of such agents. They are of particular importance in the treatment of hypertensive mammals, substantially reducing blood pressure when orally or parenterally administered thereto.

Neuronal blocking effects can be demonstrated in standard in vitro and in vivo pharmacological tests such as, for example, the rabbit jejunum test of B. Finkelman, J, PhysioL, 70, 145 (1930). In this test, electrodes are threaded to mesenteric periarterial nerves of the rabbit jejunum and the preparation is mounted in Tyrodes solution aerated with 95% oxygen and 5% carbon dioxide. Spontaneous motility is measured employing a base line tension of 1 gram and a 2 millisecond electrical pulse is then delivered to the electrodes at a frequency of 50 per second for 10 seconds. The lowest voltage is selected for each tissue which produces greater than inhibition of spontaneous motility. Antagonism of the electrical nerve stimulation expressed as percent inhibition is determined by comparison of pre-drug control response with those obtained at 7v 5, l0, l5 and 20 minute intervals after'drug addition. A blocking concentration (BC is estimated for the testdrug as the molar concentration which reduces the effect of nerve stimulation by 50% at the 20 minute exposure interval. Well known neuronal blocking agents such as guanethidine and bethanidine have a BC of 3 X '10 molar.

Results obtained in this test with representative imidazolines of the present invention are reported in Table 1. Activity is expressedas a multiple of the neuronal blocking activity of guanethidine which is taken as unity.

TABLE 1 NEURONAL BLOCKING ACTIVITY RELATlVE TO GUANETHlDlNE (=1) Ex." Chemical Name Rel. Act.

1 2-amino-4-(2-chlorophenyl)-2- 4.3

imidazoline hydrobromide 1 2-amino-4-(2-chlorophenyl)-2- 3.0

imidazoline hydrobromide levorotatory l 2-amino-4-(2-chlorophenyl)-2- 3.8

imidazoline hydrobromide dextrorotatory 2 2-benzylamino-4-(2-chlorophenyl)-2- 0.3

imidazoline hydriodidc v 3 4-(2-chlorophenyl)-2-hydrazino-2- 10.0

imidazoline hydriodide 4 4-( 2-chlorophenyl )-2-hydroxyamino-2- 1.5

imidazoline hydrochloride 5 4-(2-chlorophenyl)-2-isopropylidene- 10.0

hydrazino-2-imidazoline hydriodide g 6 2-amino-4-(4-chlorophenyl)2- 2.0

imidazoline hydrobromide 7 2-amino-4-(4-bromophenyl)-2- 0.6

imidazoline hydrobromide 8 2-amino-4-(2,4-dichlorophenyl)-2- 3.0

v imidazoline hydrobromide 9 2-amino-4-(2,6-dichlorophenyl)-2- 3.0 imidazoline hydrobromide 7 l 2-amino-4-( 3,4-dichlorophenyl )-2'- 1.5 imidazoline hydrobromide ll -2-amino-4-(m-tolyl)-2-imidazo1ine 0.43

hydrobromide l2 2-amino-4-(p-tolyl)-2-imidazoline 3.0

hydrobromide l3 2-an1ino-4-( 4-methoxyphenyl )-2- 1.0

' imidazoline hydrobromide 1'4 -2-amino-4-(4-benzyloxyphenyl)-2- 0.75

imidazoline hydrobromide l 2-amino-4-(4-biphenyl)-2-imidazoline 0.6

hydrobromide 16 Z-amino-l-benzyl-5-(2-chlorophenyl)- 0.15 Z-imidazoline h drobromide 27 2-amino 4-(3-c lorophenyl)-2- 0.03

imidazoline hydrobromide 56 2-amino-4-[3,4-dimethoxyphenyl1-2- 0.003

imidazoline hydrobromide 58 2-amino-4-( 3,4-dihydroxyphenyl)-2- 0.03

, imidazoline hydrobromide 59 2-benzylamino-4-phenyl-2-imidazoline 0.15

fumarate 60 2-(4-chlorobenzylamino)-4-phenyl-2- 0.3

imidazoline fumarate 61 2-'(3-dimethylaminopropylamino)-4- 0.003

phenyLZ-imidazoline dihydrochloride 62 2-( 2 ,6-dichlorobenzylidenehydrazino )-4- 0.03

- (2-chlorophenyl)-2-imidazoline hydriodide 63 4-(4-chlorophenyl)-2-(methylamino)-2- 0.075 imidazoline hemimucate 64 4-(4-chlorophenyl)-2-hydrazino-2- 10.0

imidazoline hydrochloride Preparation infra.

exhibits only 0.03 times the activity of guanethidine, in

this test.

Compounds of the instant invention which are partic ularly preferred for their strong neuronal blocking action are 2-amino-4-R-phenyl-Z-imidazolines wherein R is as defined above and the corresponding 2-hydrazino and 2-alkylidenehydrazino'imidazolines. There can be mentioned as particularly valuable embodiments of the present invention, the following compounds:

2-amino-4-(2-chlorophenyl)-2-imidazoline and its hydrobromide; levorotatory 2-amino-4(2-chlorophenyl)-2- imidazoline and its hydrobromide; dextrorotatory 2-amino-4-( 2-chlorophenyl )-2- imidazoline and its hydrobromide; 2-amino-4-(4-chlorophenyl)-2-imidazoline and it hydrobromide; 2-amino-4-(4-bromophenyl)-2-imidazoline and its hydrobromide; 2-amino-4-(para-tolyl)-2-imidazoline and its hydrobromide;

2-amino-4-(2,4-dichlorophenyl)-2-imidazoline and its hydrobromide; 2-amino-4-(4-biphenyl)-2-imidazoline and its hydrobromide;

2-amino-4-'( 2,6-dichlorophenyl )-2-imidazoline its hydrobromide;

'2-amino- 4-(3,4-dichlorophenyl)-2-imidazoline and its hydrobromide; 2-amino-4-(4-methoxyphenyl)-2-imidazoline and its hydrobromide; 4-(2-chlorophenyl)-2-hydrazino-2-imidazoline and its hydriodide; 4-(2-chlorophenyl)-2-isopropylidenehydrazino-Z- imidazoline and its hydriodide; 4-(2-chlorophenyl)-2-hydroxyamino-2imidazoline and its hydrochloride.

The antihypertensive effects of the imidazolines of the present invention can be demonstrated in hypertensive rats. Hypertension is produced in Sprague Dawley male rats, weighing -100 grams each, by subcutaneous administration of desoxycorticosterone acetate (DOCA) at a dose of 10 mg./rat/day for 5 days each week for 3 weeks. One percent saline is provided ad libitum for the 3-week period. At the end of the treatment period tap water is substituted for the 1% saline. Systolic blood pressures are determined by the tail cuff method, utilizing capacitance transducers for the detection of pressure, an aneroid manometer for measuring pressure, and an oscilloscope for visualizing the disappearance and/or appearance of the pressure pulse. Groups of five rats each having a systolic blood pressure of mmHg or greater are selected and the test compound administered at a dose of 5 mg./kg. subcutaneously in sterile water at a constant volume of 2.5 ml./kg. One group serves asa controland receives the water vehicle, while another receives an antihypertensive reference agent such as guanethidine sulfate, (subcutaneous dose of 20 mg./kg.) The test groups received the test agent or vehicle at 0 and 24 hr. Blood pressure and heart rate measurements are made at 0 time (immediately prior to the first dose), 4,24 (immediately prior to the second dose) 28, and 48 hr.

Data provided bythis test, includes absolute systolic blood pressures in mmHg and heart rates in beats per minute, changes in pressure and rate versus the respective time values, and percent changes in pressure and rate. By plotting the decrease in blood pressure as a function of time and determining the area under the resulting curve, an overall index of antihypertensive activity can be obtained.

and

The test agent is rated very active if either the actual blood pressure or percent decrease in pressure differed significantly (as measured by conventional statistical analysis) at all post treatment intervals. They are rated active when there is a significant difference in either the actual pressures or percent decreases in pressure at either (a) 4 and 28 hr. or (b) 24 and 48 hr. posttreatment. Test agents showing at least one random significant difference are rated slightly active and those exhibiting no significant difference are classified as inactive. On the basis of area under the percent decrease in pressure-time curve, copounds were considered very active when the area exceeded 600 units, active between 300 and 600 units, slightly active from 100 to 300 units, and inactive below 100 units.

In Table II, results obtained with representative imidazolines of the present invention are reported. The last column is a composite rating for the test agent calculated from the first three columns by (a) arbitrarily assigning numeric values of 3 (very active), 2 (active), 1 (slightly active), and (inactive) for each rating, (b) summing the assigned numeric values for actual blood pressure, percent decreases in blood pressure, and area under the time curve; and (c) applying the following ratings to those totals: very active, 8-9 (9 equals maximum score); active (4-7); slightly active (2-3); and inactive (0-1 It is to be understood that these ratings are derived from a one dose level mg./kg. body weight) assay and consequently are considered only semi-quantitative and that increasing the dosage, according to accepted pharmaceutical practice, of test agents classified herein as inactive or slightly active could product an increased antihypertensive effect.

TABLE II ANTIHYPERTENSIVE ACTIVITY RATING Activity Based On Area Under Actual 13.1. Decrease Decrease Composite Example Chemical Decrease in B.P. Time Curve Total Rating Name 1 2-amino-4-(2-chlorophenyl)-2- I I SA I 1 I imidazoline hydrobromide levorotatory (188 i 132) 1 2-amino-4-(2-chlorophenyl)-2- SA A A 5 A imidazoline hydrobromide dextrorotatory (420 i 23) 2 2-benzylamino-4-(2-chl0rophenyl)-2- I SA 1 1 I imidazoline hydriodide (52 i 45) 3 4-( 2-chlorophenyl)-2-hydrazino-2- SA SA A 4 A imidazoline hydriodide (387 t 125) 4 4-( 2-chlorophenyl)-2-hydroxyamino- SA SA SA 3 SA Z-imidazoline hydrochloride (167 t 46) 5 4-( 2-ch1oropheny1)-2-isopropy1idene- A A A 6 A hydrazino-2-imidazoline hydriodide (484 i 123) 6 2-amino-4-(4-chloropheny1)-2- SA SA A 4 A imidazoline hydrobromide (413 i 135) 7 2-amino-4-(4-bromophenyl)-2- A A A 6 A imidazoline hydrobromide (484 t 111) 8 2-amino-4-(2,4-dich1oropheny1)-2- A A A 6 A imidazoline hydrobromide (508 i 87) 9 2-amino-4-(2,6-dichlorophenyl)2- SA A VA 6 A imidazoline hydrobromide (657 i 92) 1O 2-amino-4-( 3,4-dichlorophenyl)-2- VA VA VA 9 VA imidazoline hydrobromide (121 l i 84) l l 2-amino-4-(m-tolyl)-2-imidazoline SA A 5 hydrobromide (379 i I29) 12 2-amino-4-( p-tolyl )-2-imidazoline A A A 6 A hydrobromide (425 i 34) 13 2-amino-4-( 4-methoxyphenyl)-2- SA SA A 3 SA imidazoline hydrobromide (220 i 62) 14 2-amino-4-[4-benzyloxyphenyl]-2- I I l I 0 l imidazoline hydrobromide (39 i 78) 15 2-amino-4-( 4-biphenylyl)-2- A A A 6 A imidazoline hydrobromide (415 i 49) 16 Z-amino-l-benzyl-5-(2-chlorophenyl) I I I. 0 I

-2-imidazoline hydrobromide i 66) 17 2-amino-4-(4-fluoropheny1)-2- I I I 0 I imidazoline hydrobromide (-8 i 66) 27 2-amino-4-( 3-chlorophenyI)-2- SA SA SA 3 SA imidazoline hydrobromide (157 i 56) 33 2-amin0-4-[4-(trifluoromethyl)phenyl] SA SA SA 3 SA -2-imidazo1ine hydrobromide (297 i 52) 54 2-amino-4-(3-methoxyphenyl)-2- SA I SA 2 SA imidazoline hydrobromide (178 i 121) 55 2-amino-4-I 3-( benzyloxy )phenyl ]-2- A A A 6 A imidazoline hydrobromide (391 i 58) 56 2-amino-4-l3,4-dimethoxyphenyl1-2- SA A A 5 A imidazoline hydrobromide (394 i 69) 57 2-amino-4-(3-hydroxypheny1)-2- SA A A 5 A imidazoline hydrobromide (505 i 96) 58 2-amino-4-(3,4-dihydroxyphenyl)-2- A SA VA 6 A imidazoline hydrobromide (619 i 96) 59 2-benzylamino-4-pheny1-2- SA SA A 4 A imidazoline fumarate (325 i 82) 60 2-(4-chlorobenzylamino)-4-phenyl- A A VA 7 A 2-imidazoline fumarate (612 i 71) 61 2-( 3-dimethy1aminopropylamino)-4- SA SA SA 3 SA phenyl-Z-imidazoline dihydrochloride (268 i 119) 62 2-(2,6-dichlorobenzylidenehydrazino) A A A 6 A -4-(2-chloropheny1)-2-imidazo1ine (450 i 66) hydriodide 63 4-(4-chlorophenyl)-2-(methylamino) VA A A -2-imidazoline hemimucate ferred fortheir potent antihypertensive effects are:

2-amino-4-(4-chlorophenyl)-2-imidazoline and its hydrobromide. 2-amino-4-(3,4-dichlorophenyl)-2-imidazoline and its hydrobromide, 4-(2-chlorophenyl)-2-isopropylidene hydrazino-2- imidazoline and its hydriodide, 2-amino-4-(2,6-dichlorophenyl)-2-imidazoline its hydrobromide, 2-amino-4-[3,4-dimethoxyphenyl]-2-imidazoline and its hydrobromide, 4-(4-ch1orophenyl)-2-(methylamino)-2-imidazoline and its hemimucate, 2-(4-chlorobenzylamino)-4- phenyl-2-imidazoline and its fumarate.

The known art imidazoline, 2-amino-4-phenyl-2- imidazoline at a 5 mg./kg. body weight subcutaneous dose has no demonstrable activity in the DOCA hypertensive rat model and is considered to be essentially inactive.

The antihypertensive and neuronal blocking therapeutic process of the present invention is carried out in mammals by systemic administration of a non-toxic effective dose of the imidazolines of the present invention ranging from about 0.01 to 50 milligram per kilogram of body weight of the mammal. By systemic administration it is intended to include both oral and parenteral routes. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal and subcutaneous administration. The dosage will vary with the form of administration and particular compound chosen. Generally, the compound is administered at a dosage substantially less than the dose of the compound which is thought to be effective. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. As a general rule, it will be found that when the composition is administered orally, larger quantities of the imidazoline will be required to produce the same effect as the and smaller quantity given parenterally. In general, the

compounds of this invention .are most desirably administered ata concentration level that will afford effective results without causing any harmful or deleterious side effects.

The compounds which constitute this invention and their methods of preparation will appear more fully from a considerationof the following examples which are given for the purpose of illustration only and are not to be construed as limiting the invention in spirit or in scope.

TABLE ll Continued ANTIHYPERTENSIVE ACTIVITY RAT1NG' Activity Based On Area Under I g Actual B.P. Decrease Decrease Composite. Example Chemical Decrease in HP. Time Curve Total Rating Name 1 64 4-(4chl0rophenyl)-2-hydrazino-2- A SA A 5 A imidazoline hydrochloride (336 i 68) Numerical Rating Abbreviation Value Very VA 3 Active Active A 2 Slightly SA 1 Active Inactive l 0 Preparation infra.

Compounds of the present invention particularly'pre-. EXAMPLE 1.

2-Amino-4-( 2-chlorophenyl )-2-imidazoline hydrobromide.

An aqueous solution of l-(2-chlorophenyl)ethylenediamine dihydrochloride (8.8 g., 0.04 mole) is made basic with 50% sodium hydroxide and the free base isolated by extracting the basified solution with chloroform, drying the chloroform extract over potassium carbonate and concentrating under reduced pres sure. The free base thus obtained is'taken up in 100 ml.

- of benzene and treated with a solution of cyanogen bromide (4.2 g., 0.04 mole) in ml. of benzene. After stirring for 4 hrs. at roomtemperature, the mixture is filtered and the filter-cake washed with benzene to provide 9.1 g., (92% yield) of 2-amino-4-(2-chlorophenyl) 2-imidazoline hydrobromide having a melting point of l90-200C. Crystallization of this material from absolute ethanol-isopropyl ether affords 7.0 g. of analytically pure product, m.p. 213.5215.5C. (corr.).

Analysis. Calcd. for C H, C1N .HBr (percent): C, 39.08; H, 4.01; N, 15.19. Found.(percent): C, 38.92; H, 4.08; N, 15.07. I.

Reaction of d-l-(2-chlorophenyl)ethylenediamine obtained from d-1-(2-chlorophenyl)ethylenediamine l-tartrate (5.0 g., 0.0155 mole) with 1.8 g. of cyanogen bromide in 50 ml. of benzene according to the above procedure and crystallization of the imidazoline obtained from absolute ethanol-isopropyl ether provides analytically pure l-2-'amino-4'-(2-chlorophenyl)-2' imidazoline hydrobromide,.m.p. 1609-1 62.5C. (corn);

EXAMPLE 2.

2-Benzylamino-4-(2-chlorophenyl)-2-imidazoline hydriodide.

A mixture of 2-methylthio-4-(2-chlorophenyl)-2- 14 To 2-methylthio-4-(2-chlorophenyl)-2-imidazoline hydriodide (7.09 g., 0.02 mole) in 25 ml. of methanol is added 'a solution of methanolic sodium methoxide prepared by the addition of sodium (0.46 g., 0.02

5 mole) to 25 ml. of methanol. The mixture is concenlmldazollne hydriodide mole) and l' trated under reduced pressure and the residue taken up amine (214 mole) in 75 of isopropanol in anhydrous ether, filtered, and the filtrate concenrefluxed for 44 At this Point an additional equiva' trated in vacuo. The resulting oily residue solidifies on lent of benzylamine is added reflux continued for scratching and is triturated with ether to provide 4.1 g. other 6 hrs. and the mixture then concentrated under of 2 methy]thi0 4 (2 ch]0mpheny|) 2 imidazo]ine, reduced pressure. The residual oil shaken with 1:1 mixture of water-ether solidifies on standing, and is col- Reaction of 2 methy]thio 4 (2 ch]oi0phenyl) 2 lected, triturated with ether and dried to provide 5.3 g. imidazoline 4 g" 0018 mole) with hydroxylamine of product having a meltmg pomt of l3O"135C' Crys' drochloride (1.39 g., 0.02 mole) in 50 ml. of absolute tallization of this material from absolute ethanolethanol according to the procedure f Example 2 p py ether affords analytlcally P vides 4-( 2-chlorophenyl)-2-hydroxyamino-2- benzylamlno'4'(z'chlorophenyll'z'imidazoline hydrio' imidazoline hydrochloride. An analytical sample obdide 147214900 tained by crystallization from acetonitrile-methanol has Analysis. Calcd. for C H ClN fil (percent): C, a melting point 1 '5 (corny 46.45; H, 4.14; N, 10.15. Found (percent): C, 46.18; Analysis Calcd f C9H10Q1N3OHC] (percent); C, ll, 411; N, 43.56; 11, 4.47; N, 16.94. Found (percent):'C, 43.50;

EXAMPLE 3. H, 4.64; N, 16.88.

4-(2-Chlorophenyl)-2-hydrazino-2-imida2oline EXAMPLE 5 hydriodide' 4 2 Ch] h 1) 2 0 lidene Hydrazine hydrate (85%, 39 g., 0.05 mole) is added h) draZin ;l:i nigg'azon 11101;; dpyodide' in one port1on to 2-methylth1o-4-(2-chlorophenyl)-2- imidazoline hydriodide 17.7 g., 0.05 mole) in 200 ml. T a h solution of p y y of absolute ethanol. The mixture is refluxed for a 6 hr. z-lmldalollfle hydriodide g6 mole) in period and then concentrated in vacuo to provide a re- 30 of water is added 1 of acetone and 3 drops of sidual oil which is successively taken up in absolute ethacetic acld- The mixture is refluxed for llli, Cooled, anol and reconcentrated until a solid is obtained. Trituand filtered to p of analytically P ration of the solid with absolute ethanol provides 13.2 cllloropllenyll-2-lsopl'opylldene y g. (78% yield) of material having a melting point of lmldalollne hydriodide, -P- 175-182C., crystallization from isopropyl alcohol- Analysls- Calcll 12 15 4- (P isopropyl ether provides analytically pure 4-(2- H, N, Found (P C, 3815; chlorophenyl)-2-hydrazino-2-imidazoline hydriodide. N, 6-

Anal sis. Calcd. for C H C1N .Hl ercent): C, 31.92; 11, 3.57; N, 16.55. Found (percen t): c, 31.93; EXAMPLES H, 3.58; N, 16.74. Other representative examples of the compounds of the present invention prepared according to the proce- EXAMPLE dure described in Example 1 from the indicated 4-(2-Ch1orophenyl)-2-hydroxyamino-2-imidazoline phenylethylenediamine reactants are enumerated in hydrochloride the following table.

E li-L E IMIDAZOLINES Example Phenylethylenediamine Reactant R M.P.C. Formula Calcd. Found 6 1-(4-Chlorophenyl)- 4-Cl H 241-242 C H, ClN;,.HBr C 39.08 C 38 .87 ethylenediamine H 4.01 H 4.22 N 1 5. 19 N 1 5.02 7 1-( 4-Bromophenyl)- 4-Br H 239-2405 C H BrN .HBr C 33.67 C 33.76 ethylenediamine H 3.45 H 3.46 I N 1 3.09 N 1 3.20 8 1-( 2,4-Dichlorophenyl)- 2,4-d1Cl H 198.5200.5 C H Cl;N;,.HBr C 34.75 C 35 .00 ethylenediamine H 3.24 H 3 .08 N 13.5 1 N 1 3 .50 9 1-( 2,6-Dichlorophenyl)- 2,6-d1Cl H 233-235 C H Cl N .HBr C 34.75 C 34.97 ethylenediamine 4 H 3.24 H 3.17 N 1 3 .5 1 N 13.6 1 10 1'( 3,4-Dichlorophenyl)- 3,4-d1C1 H 213-215 C H Cl- N .HBr C 34.75 C 35.02 ethylenediamine H 3.24 H 3.22 N 13.5 1 N 1 3 .27 1 1 1-( 3-Methylphenyl)- 3CH;, H 148-149 C H N .HBr C 46.89 C 47.04 ethylenediarnme H 5.51 H 5.56 N 16.40 N 16.33 12 1-( 4-Methylphenyl)- 4CH H -187.5 C ,,H N .HBr C 46.89 C 46.63 ethylenedlamine H 5.5 l H 5.3 1 N 16.40 N 1 6. 14

EXAMPLE 54.

Cyclization of l-(3-methoxyphenyl)ethylenediamine with cyanogen bromide is carried out according to the procedure of Example 1. The analytically pure product (from acetonitrileisopropyl ether) has a melting point of 150.0-151.5C. (corr.).

Analysis. Calcd. for C H N .HBr (percent): C,

44.14; H, 5.18; N, 15.44. Found (percent): C, 44.50;

EXAMPLE 55.

2-Amino-4-[3-( benzyloxy)phenyl]-2-imidazoline hydrobromide. Cyclization of l-(3-benzyloxyphenyl ethylenediamine is carried out according to the procedure of Example 1. The analytically pure product (from ethyl acetate) has a melting point of l78.5-180.5C. (corr.).

Analysis. Calcd. for C, H N .HBr (percent): C,

- 55.18; H, 5.21; N, 12.07. Found (percent): C, 55.45;

EXAMPLE 56.

2-Amino-4-[ 3,4-dimethoxyphenyl]-2-imidazoline hydrobromide. Cyclization of l-( 3 ,4-dimethoxyphenyl)- EXAMPLE 57.

2-Amino-4-(3-hydroxyphenyl)-2-imidazoline hydrobromide.

2-Amino-4-[3-(benzyloxy)phenyl]-2-imidazoline hydrobromide is debenzylated in a Parr apparatus employing 10% palladium on carbon catalyst in ethanol. The analytically pure product (from acetonitrile) has a melting point of 119.5-122.5C. (corr.).

Analysis. Calcd. for C H, N O.HBr (percent): C,

41.87; H, 4.69; N, 16.28. Found (percent): C, 41.62; H, 4.76; N, 15.99.

EXAMPLE 5 8 2-Amino-4-( 3 ,4-dihydroxyphenyl )-2-imidazpline hydrobromide. Cyclization of 1-( 3 ,4-dibenzyloxyphenyl )ethylenediamine with cyanogen bromide carried out according to the procedure of Example 1 provides 2- amino-4- 3 ,4-dibenzyloxyphenyl -2-imidazoline drobromide. The dibenzyloxy imidazoline is debenzylated in methanol employing 10% palladium on carbon catalyst. The analytically pure product (from me- 20 thanol-acetonitrile') -.a melting point 167.5169.5C. (corr): 7

Analysis. Calcd. for C H N O .HBr (percent): C,

ExAMPLE'59. 2-Benzylamino-4-phenyl-2rimidazolinefumarate.

A mixture of 2-methylthio-4-phenyl-2-imidazoline hydriodide (8.0 g., 0.025 mole) and benzylamine (2.68 g., 0.025 mole) in ml. of is opropanol is refluxed for two days and the mixture concentrated. The residual oil is stirred with 200 ml. of hot water, water insoluble material separated, and the aqueous solution made basic with sodium hydroxide, extracted with chloroform, and the chloroform extract dried over potassium carbonate. Concentration of the dried chloroform extract provides an oil which is'taken up in absolute ethanol and acidified with fumaric acid. Addition of isopropyl ether to the acidified solution proyides the imidazoline product 4.5 g., m.p. 2035 205C. Crystallization from methanol-ethanol provides analytically pure 2- benzylamino-4-phenyl-2-imidazoline fumarate, m.p. 203204C. (corr.). A

Analysis. Calcd. for C H N .1/2 C H O (percent): C, 69.88; H, 6.19; N, 13.58. Found (percent): C, 70.03; H, 6.27; N, 13.63.

EXAMPLE 60.

2-(4-Chlorobenzylamino)-4-phenyl-2-imidazoline fumarat'e.

Reaction of 2-methylthio-4-phenyl-2-imidazoline hydriodide with 4-ch1orobenzylamine is carried out according to the procedure of Example 59. The analytically pure product (from'acetone) has a melting point of 180.5182.5C. (dec.) (corr.).

Analysis. Calcd. for C H ClN .1/2C H O (percent): C, 62.88; H, 5.28; N, 12.22. Found (percent): C,

' EXAMPLE 62.

- 2-(2,6-Dichlorobenzylidenehydrazino) 4-(2-chlorophenyl).-2- imidazoline hydriodide. H

An equiniolar mixture of 4-(2=chlorophenyl)-2- hydrazine-'2-imidazoline hydriod ide' and 2,6- dichlorobenzaldehyde in 50 ml. of absolute ethanol with a'catalytic amount of acetic acid is refluxed for 18 hr. and then concentrated under reduced pressure. Trituration of the residue thus obtained with ethanol provides the imidazoline product which is crystallized from acetonitrile-isopropyl ether to analytical purity, m.p. 209.5-2l0.5C. (corr.).

Analysis. Calcd. for C, H C1 N .Hl (percent): C, 38.77; H, 2.85; N, 11.30. Found (percent): C, 38.50; H, 2.79; N, 11.46.

EXAMPLE 63.

4-( 4-Chlorophenyl)-2-(methylamino)-2-imidazoline hemimucate.

A mixture of 2-methylthio-4-(4-chloropheny1)- Z-imidazoline (5.65 g., 0.025 mole) and methylamine hydrochloride (1.75 g., 0.025 mole) in 100 ml. of isopropanol is refluxed for hr. and then concentrated under reduced pressure. The residual oil is taken up in water, converted to the free base with sodium hydroxide and extracted with chloroform. After drying the chloroform extract over potassium carbonate, the chloroform solvent is removed and the residue taken up in refluxing methanol. Mucic acid (2.6 g.) is added to the hot solution and the mixture filtered. Concentration of the filtrate and trituration of residue with hot acetone provides a solid which is crystallized from methanolisopropyl ether to provide analytically pure product, m. p. l79.5l80.5C. (dec.) (corr.).

Analysis. Calcd. for C H ClN l/2 C H O (percent): C, 49.60; H, 5.44; N, 13.35. Found (percent): C, 49.35; H, 5.53; N, 13.26.

EXAMPLE 64.

4-(4-Chlorophenyl)-2-hydrazino-2-imidazoline hydrochloride.

-2-Methylthio-4-(4-chlorophenyl)-2-imidazoline hydriodide (8.9 g., 0.025 mole) and 2 g. of 85% hydrazine hydrate in 75 ml. of isopropyl alochol is refluxed for about 6 hr. and then concentrated under reduced pressure. Trituration of the residue with ethyl acetate provides 4-(4-chlorophenyl)-2-hydrazino-2-imidazoline hydriodide, m.p. l25l27C. The imidazoline hydriodide is passed through an ion exchange column to convert it to the hydrochloride salt. The hydrochloride salt crystallized from ethyl acetate-methanol provides analytically pure 4-(4-chlorophenyl)-2-hydrazino-2- imidazoline hydrochloride, m.p. 155 .51 57.5C. (corr.).

Analysis. Calcd. for C H CIN .HCl (percent): C, 43.74; H, 4.90; N, 22.67. Found (percent): C, 43.51; H, 5.09; N, 22.56.

EXAMPLE 65.

4-(4-Chlorophenyl)-2-(benzylamino)-2-imidazoline hydriodide.

Reaction of 2-methylthio-4-(4-chlorophenyl)- 2-imidazoline hydriodide and benzylamine according to the procedure of Example 59 and preparation of the hydriodide salt according to Example 63 affords 4-(4- chlorophenyl)-2-(benzylamino)-2-imidazoline hydriodide, m.p. l18.5-120.5C. (corr.) (from isopropanolisopropyl ether).

Analysis. Calcd. for C, H ClN .HI (percent). C, 46.45; H, 4.14; N, 10.16. Found (percent): C, 46.23; H, 4.23; N, 10.08.

EXAMPLE 66.

4-(4-Chlorophenyl)-2-(4-chlorobenzylamino- 2-imidazoline hydriodide.

Reaction of 2-methylthio-4-(4-chlorophenyl)- 2-imidazoline hydriodide and 4-chlorobenzylamine according to the method of Example 59 provides the imidazoline, 4-(4-ch1orophenyl)- 2-(4-chlorobenzylamino)-2-imidazo1ine hemimucate m.p. 126128C. (from acetonitrile). Neutralizing the imidazoline hemimucate with base and acidifying the base in an inert solvent with HI provides:

4-(4-chlorophenyl)-2-(4-chlorobenzylamino- 2-imidazoline hydriodide, m.p. 152-l54C. (from acetonitrile-isopropyl ether).

EXAMPLE 67.

4-( 3 ,4-Dichlorophenyl)-2-( 3,4-dichlor0benzylamino)- 2-imidaz0line hydriodide.

-Reaction of 2-methylthio- 4-(3,4-dichlorophenyl)-2-imidazoline hydriodide and 3,4-dichlorobenzylamine according to the method of Example 59 provides the imidazoline product, m.p. l71-l73C. (corr.) (from ethyl acetate).

Analysis. Calcd. for CISHI3CI4N3-HI (percent): C, 37.16; H, 2.73; N, 8.13. Found (percent): C, 36.94; H, 2.80; N, 8.09.

EXAMPLE 68.

4-(3 ,4-Dichlorophenyl)-2-( 4-chlorobenzylamino-2- imidazoline hydriodide.

-Reaction of 2-methy1thio-4-(3,4-dichlorophenyl)- 2-imidazoline hydriodide and 4-chlorobenzylamine according to the method of Example 59 provides the imidazoline, 4-(3,4-dichlorophenyl)-2-(4-chlorobenzylamino)-2-imidazoline. The hydriodide salt is prepared from the imidazoline base by acidifying with H1 in an inert solvent and has a melting point of 1 16-1 19C. (corr.) (from isopropanol-isopropyl ether).

Analysis. Calcd. for C H Cl N .Hl (percent): C, 39.82; H, 3.13; N, 8.71. Found (percent): C, 39.87; H, 3.14; N, 8.64.

EXAMPLE 69.

4-( 3 ,4-Dichlorophenyl)-2-(allylamino)-2-imidazoline.

ample EXAMPLE 70. 4-( 3 ,4-Dichlorophenyl)-2-(cycloprcpyiamino} 2-imidazoline.

EXAMPLE 71.

4-( 3 ,4-Dichlorophenyl )-2-( benzyl )-2-imidazoline hydriodide.

' Reaction of 2-methylthio-4-(3,4-dichlorophenyl)- 2-imidazoline hydriodide and benzylamine according to the method of Example 59 provides the imidazoline, 4-(3,4-dichlorophenyl)- 2-(benzylamino)-2-imidazoline hydriodide, 151.5153C. (corn) (from ethyl acetate).

Analysis. Calcd. for C H Cl N .HI (percent): C,

42.88; H, 3.60; N, 9.38. Found (percent): C, 43.05; H,

EXAMPLE 72.

4-(4-Chlorophenyl)-2-(3,4-dichlorobenzylamino)- 2-imidazoline hydriodide.

Reaction of 2-methylthio-4- (4-chlorophenyl)-2-imidazoline hydriodide and 3,4-

dichlorobenzylamine according to the method of Ex- 59 provides the imidazoline, 4-(4- chlorophenyl)-2-(3,4-dichlorobenzylamino)-2- imidazoline. The hydriodide salt is prepared from' the imidazoline base by acidifying with HI in inert solvent and has a melting point of 152-l54C. (corr.) (from ethyl acetate).

Analysis. Calcd. for C H Cl N fil (percent): C, 39.82; H, 3.13; N, 8.71. Found (percent): C, 39.61; H,

STARTING MATERIALS The various phenylethylenediamines employed in the foregoing examples and intermediates required for their preparation are obtained by methods described as follows.

A. PREPARATION OF a-AMINOPHENYLACETONITRILES 1. a-(Benzylamino)-2-chlorophenylacetonitrile hydrochloride.

2-Chlorobenzaldehyde (154.3 g., 1.1 mole) in 400 ml. of methanol is added in one portion to sodium cyanide (54 g., 1.1 mole) and benzylamine hydrochloride (158 g., 1.1 mole) in 400 ml. of water. The mixture is stirred for a period of 5 hr. and then diluted with one liter of water. The diluted mixture is extracted with four 500 ml. portions of ether, the ether extracts combined and dried over potassium carbonate. Acidification of the ethereal extract with ethanolic hydrogen chloride provides 269 g., of a-(benzylamino)-2- chlorophenylacetonitrile having a melting point of 149l56C. Crystallization from acetone-isopropyl ether provides material with a melting point of l54-156C.

Analysis. Calcd.: C, 61.44; H, 4.81; N, 9.56. Found:'

C, 62.21; H, 4.92; N, 9.68.

Following the procedure described above for a-(benzylamino)-2-chlorophenylacetonitrile hydrochloride but employing equimolar amounts of the following benzaldehydes:

2,4-dichlorobenzaldehyde,

3-methylbenzaldehyde,

4-methylbenzaldehyde,

4-methoxybenzaldehyde,

4-biphenylcarboxaldehyde,

3-chlorobenzaldehyde,

3-trifluoromethylbenzaldehyde,

4-trifluoromethylbenzaldehyde, in place of 2-chlorobenzaldehyde, there is produced:

2. a-(benzylamino)-2,4-dichlorophenylacetonitrile hydrochloride, m.p. 138-144C.; 3. a-( benzylamino )-3-methylphenylacetonitrile hydrochloride, m.p. l66-170C.; 1 4. a-(benzylamino)-4-methylphenylacetonitrile hydrochloride, m.p. l29l32C. 5. a-(benzylamino)-4-methoxyphenylacetonitrile hydrochloride; 6. a-(benzylamino)-4-biphenylacetonitrile hydrochloride, m.p. 150152C.; 7. a-(benzylamino)-3-chlorophenylacetonitrile hydrochloride, m.p. 172l78C.; 8. a-(benzylamino)-3-trifiuoromethylphenylacetonitrile hydrochloride; a-(benzylamino)-4-trifluoromethylphenylacetonitrile hydrochloride.

l0. a-Amino-4-chlorophenylacetonitrile hydrochloride.

A mixture of 4-chlorobenzaldehyde (80 g., 0.57 mole) and sodium bisulfite (59.2 g., 0.57 mole) in 300 ml. of water is stirred for 1.5 hr. at room temperature and then heated to C. for 0.5 hr. Ammonium hydroxide (15N, 38 ml., 0.57 mole) is rapidly added to the mixture and stirring continued for 0.5 hr. at 60C After cooling the mixture to below 10C., a solution of sodium cyanide (28 g., 0.57 mole) in ml. of water is added over a 10 minute period and stirring continued for an additional 2.5 hr. at room temperature. Extraction of the mixture with chloroform, drying the chloroform extract over potassium carbonate and concentrating under reduced pressure provides a residual oil. The oil is taken up in 50 ml. of absolute ethanol and acidified with ethanolic hydrogen chloride. On additon of isopropyl ether, a precipitate forms which is collected and washed with isopropyl ether to provide 18.1 g. of a-amino-4-chlorophenylacetonitrile hydrochloride having a melting point of l74l75C.

Analysis. Calcd.: C, 47.31; H, 3.97; N, 13.80. Found: C, 47.52; H, 4.05; N, 13.69.

11. a-Amino-4-bromophenylacetonitrile hydrochloride.

To a slurry of sodium cyanide (13.2 g., 0.27 mole) and ammonium chloride (14.4 g., 0.027 mole) in ml. of 1:9 water-dimethylsulfoxide ,is added 4- bromobenzaldehyde (25 g., 0.135 mole) in 150 ml. of dimethylsulfoxide in one portion. The mixture is stirred for 5 hr. and then quenched in 1.5 liters of water. Extraction of this mixture with ether, drying the ethereal extract over potassium carbonate and then acidifying with ethanolic hydrogen chloride provides a-amino-4- bromophenylacetonitrile hydrochloride, m.p. 180-l82C.

12. a-Amino-4-benzyloxyphenylacetonitrile.

A solution of 4-benzyloxybenzaldehyde (41.5 g., 0.195 mole) in 400 ml. of acetonitrile is added in one portion to a solution of sodium cyanide (9.6 g.) and ammonium chloride (11.7 g.) in 400 ml. of water. The mixture is stirred overnight, filtered and the filter-cake washed with water to provide 1 1.1 g. of a-amino-4-benzyloxyphenylacetonitrile free base, m.p. 108-l 12C.

a-Amino-4-benzyloxyphenylacetonitrile hydrochloride prepared from the free base is purified by crystallization from absolute ethanol-isopropyl ether, m.p. 178-179C.

Analysis. Calcd.: C, 65.57; H, 5.50; N, 10.20. Found: C, 65.37; H, 5.21; N, 9.96.

13. a-Amino-Z,6-dichlorophenylacetonitrile hydrochloride.

In the manner given above for (12) a-amino-4-benzyloxyphenylacetonitrile but employing methanol in place of acetonitrile, 2,o-dichlorobenzaldehyde, ammonium chloride, and sodium cyanide were reacted to give a-amino-2,6,dichlorophenylacetonitrile hydrochloride, m.p. 192200C.

14. a-Amino-3,4-dichlorophenylacetonitrile hydrochloride.

In the manner given above for (11) a-amino-4- bromophenylacetonitrile, 3,4-dichlorobenzaldehyde, ammonium chloride and sodium cyanide were reacted to give a-amino-3,4-dichlorophenylacetonitrile hydrochloride, m.p. 184185C.

15. a-(Benzylamino)-4-fluorophenylacetonitrile hydrochloride.

- In the manner given above for l) a-(benzylamino)- 2-chlorophenylacetonitrile hydrochloride, 4- fluorobenzaldehyde substituted for 2- chlorobenzaldehyde provides oz-(benzylamino)-4- fluorophenylacetonitrile hydrochloride, m.p. 1 27-1 30C 16. oz-( Benzylamino)-4-trifluoromethylphenylacetonitrile hydrochloride.

In the manner given above for (1) a-(benzylamino)- 2-chlorophenylacetonitrile hydrochloride, 4-trifluoromethylbenzaldehyde provides a-(benzylamino)-4-trifluoromethylphenylacetonitrile hydrochloride, m.p. 152158C.

l7. a-(Benzylamino)-3-methoxyphenylacetonitrile hydrochloride.

In the manner given above for (1) oz-(benzylamino)- 2-chlorophenylacetonitrile hydrochloride, 3- methoxybenzylaldehyde provides a-(benzy1amino)-3- methoxyphenylacetonitrile hydrochloride, m.p. 155-l58C.

18. a-Amino-3-benzyloxyphenylacetonitrile hydrochloride.

In the manner given above for (11) a-amino-4- bromophenylacetonitrile hydrochloride, 3-benzyloxybenzaldehyde provides a-amino-3-benzyloxyphenylacetonitrile hydrochloride, m.p. 150160C.

19. a-Amino-3,4-dimethoxyphenylacetonitrile hydrochloride.

In the manner given above for (10) a-amino-4- chlorophenylacetonitrile hydrochloride, 3,4-dimethoxybenzaldehyde provides a-amino-3,4-dimethoxyphenylacetonitrile hydrochloride, m.p. l73-175C. Crystallization from isopropyl ether-absolute ethanol affords analytically pure material, m.p. 173175C. (corn) v Analysis. Calcd. (percent): C, 52.52; H, 5.73; N, 12.25. Found (percent): C, 52.81; H, 5.60; N, 12.19.

20. a-Amino-3,4-dibenzyloxyphenylacetonitrile hydrochloride.

In the manner given above for (11) a-amino-4- bromophenylacetonitrile hydrochloride, 3,4-dibenzyloxybenzaldehyde provides a-amino-3,4-dibenzyloxyphenylacetonitrile hydrochloride, m.p. 168-171C.

B. Preparation of l-Phenylethylenediamines 1. 1-(2,6-Dichlorophenyl)ethylenediamine dihydrochloride.

a-Amino-Z,6-dichlorophenylacetonitrile hydrochloride (24 g., 0.1 mole) is converted to the free base with 10% sodium hydroxide. To a tetrahydrofuran solution (350 ml.) of the free base (24 g., 0.1 mole) is added 225 ml. of 1 molar diborane in tetrahydrofuran over a period of 0.5 hr. under a nitrogen atmosphere. After stirring for 0.5 hr., the mixture is first hydrolyzed by the careful addition of 100 ml. of water and then concentrated under reduced pressure to provide an oil. This residual oil is taken up in ethanol and acidified with ethanolic hydrogen chloride (36 ml., 5.6N, 0.2 mole). Evaporation of the acidified solution under reduced pressure and treatment with 10 percent sodium hydroxide provides the free amine which is isolated by extracting the basified mixture with chloroform, drying the chloroform extract over potassium carbonate, and concentrating in vacuo. The residual oil thus obtained is taken up in ethanolic hydrogen chloride (27 ml., 5.6N, 0.15 mole) and diluted with an equal volume of isopropyl ether to provide 19.0 g., (68%) of l-(2,6- dichlorophenyl)ethylenediamine dihydrochloride, m.p. 329-331C.

Following the proceduredescribed above for 1-(2,6- dichlorophenyl)ethylenediamine dihydrochloride but employing equimolar amounts of the following a-aminophenylacetonitriles:

7. B-(Benzylamino)-2-chlorophenethylamine dihydchloride is converted to the free base by treatment with 10% sodium hydroxide. A solution of a-benzylamino-Z- chlorophenyl-acetonitrile (64.2 g., 0.25 mole) in.500 ml. of anhydrous ether is added to a stirred suspension of lithium aluminum hydride (38 g., 1 mole) in 1 liter of anhydrous ether under a nitrogen atmosphere over a 0.5 hr. period at C. After the addition is complete, the mixture is stirred at 0C. for hr. and then at room temperature overnight. Hydrolysis of the reaction mixture is carried out by the sequential addition of water (38 ml.), 15% sodium hydroxide (38 ml.) and a 70 ml. portion of water. Filtration of the mixture removes inorganic material and addition of 5N ethanolic hydrogen chloride (130 ml., 0.65 mole) to the filtrate provides 82 g., (97%) of B-(benzylamino)-2- chlorophenethylamine dihydrochloride, m.p. 216-2l9C.,

Following the procedure described above for B-benzylamino-2-chlorophenethylamine dihydrochloride but employing equimolar amounts of the following 2- (benzylamino)phenylacetonitriles:

a-(benzylamino)-2,4-dichloropheny1acetonitrile,

a-(benzylamino)-3-methylphenylacetonitrile,

'a-(benzylamino)-4-methylphenylacetonitrile,

a-(benzylamino)-4-methoxyphenylacetonitrile,

a-(benzylamino)-4-biphenylacetonitrile, a-(benzylamino)-3-chlorophenylacetonitrile, a-amino-3,4-dichlorophenylacetonitrile, in place of a(benzylamino)-2- chlorophenylacetonitrile, there is produced:

8. B-(benzylamino)-2,4-dichlorophenethy1amine dihydrochloride, m.p. 239-24lC.;

9. B-(benzylamino)-3-methylphenethylamine dihydrochloride, m.p. 175-180C.;

l0. B-(benzylamino)-4-methylphenethylamine dihydrochloride, m.p. 3l2-315C.;

ll. /3-(benzylamino)-4-methoxyphenethylamine dihydrochloride;

12. fl-(benzylamino)-4-biphenylethylamine dihydrochloride, m.p. 257259C.;

l3. B-(benzylamino)-3-chlorophenethylamine dihydrochloride, m.p. 225230C.;

14. B-amino-3,4-dichlorophenethy1amine dihydrochloride, m.p. 283-285C.

l5. 1-(2-Chlorophenyl)ethylenediamine dihydrochloride.

A suspension of B-(benzylamino)-2- chlorophenethylamine dihydrochloride (33.4 g., 0.1 mole) in 200 ml. of methanol is debenzylated by hydrogenating over palladium on carbon catalyst at 50 p.s.i. or atmospheric pressure in a hydrogenation apparatus. Before charging the hydrogenation vessel with the catalyst, the catalyst is first treated in a beaker with small portions of methanol. The method solvent is allowed to ignite and the flame is immediately smothered Analysis. Calcd.: C, 39.45; H, 5.38; N, 11.50. Found: C, 39.52; H, 5.47; N, 11.58.

Two equivalents of d-camphorsulfonic acid is added to one equivalent of dl-(2-chlorophenyl)ethylenediamine in ethanol. Successive crystallizations from ethanol affords optically pure l-l-(2-.chlorophenyl)ethylenediamine di-d-camphorsulfonate salt, m.p. 244-248C.; [01],, 6.5 (C 1, H O).

The d-camphorsulfonate mother liquors which are enriched with the d-diamine are concentrated under reduced pressure and the residue converted to free diamine with 10% sodium hydroxide and then to the 1- tartaric acid -salt. Successive crystallizations for ethanol-water affords optically pure d-l-(2-chlorophenyl)ethylenediamine l-tartrate salt, m.p. 206-209C.; [01],, 5.0 (c 1, H O).

Following the procedure described above for l-(2- chlorophenyl)ethylenediamine dihydrochloride but employing equimolar amounts of the following B-benzylaminophenethylene dihydrochlorides:

B-( benzylamino)-2,4-dichlorophenethylamine dihydrochloride, v B-(benzylamino)-3-methy1phenethylamine dihydrochloride, B-(benzylamino)-4-methylphenethylamine dihydrochloride, B-(benzylamino)-4-methoxyphenethylamine dihydrochloride,

B-( benzylamino )-4-biphenylethylamine dihydrochloride, B-(benzylamino)-3-chlorophenethy1amine dihydrochloride, [3-(benzylamino)-3-trifluoromethylphenethylamine dihydrochloride,

B-(benzylamino)-4-trifluoromethylphenethylamine dihydrochloride, in place of /3-(benzylamino)-2-chlorophenethylamine dihydrochloride, there is produced:

(16). l-(2,4-dichlorophenyl)ethylenediamine dihydrochloride, m.p. 305310C.;

17. l-( 3-methylphenyl )ethylenediamine dihydrochloride, m.p. 238-243C.;

1 8. l-(4-methylphenyl )ethylenediamine dihydrodihydrohydrochloride;

23. 1-(4-trifluoromethylphenyl)ethylenediamine dihydrochloride.

24. 1-(4-Fluorophenyl)ethylenediamine dihydrochloride, m.p. 255265C. Prepared by debenzylation of B-(benzylamino)-4-fluorophenethylamine dihydrochloride, m.'p. 229232C., obtained by lithium aluminum hydride 'reduction of a-(benzylamino)4- fluorophenylacetonitrile.

25. l-(4-Trif1uoromethylpheny1)ethylenediamine dihydrochloride, m.p. 259261C. Prepared by debenzylation of B-(benzylamino)-4-trifluoromethylphenethylamine, m.p. 242.5245C. obtained byreduction of B-(benzylamino)-4-trifluorophenylacetonitrile with diisobutyl aluminum hydride.

26. l-(3-Methoxyphenyl)ethylenediamine dihydrochloride, m.p. 245-250C. Prepared by debenzylation of B-(benzylamino)-3-methoxyphenethylamine dihydrochloride obtained by reduction of oz-(benzylamino)- 3-methoxyphenylacetonitrile with lithium aluminum hydride.

27. l-(3-Benzyloxyphenyl)ethylenediamine dihydrochloride m.p. 225-235C. prepared by reduction of a-amino-3-benzyloxyphenylacetonitrile with lithium aluminum hydride.

28. l-( 3 ,4-Dimethoxyphenyl )ethylenediamine dihydrochloride, m.p. 25826lC. Prepared by catalytic reduction of a-amino-3,4-dimethoxyphenylacetonitrile hydrochloride employing platinum oxide in ethanol with a molar equivalent of hydrogen chloride.

29. 1-(3,4-Dibenzyloxyphenyl)ethylenediamine dihydrochloride, m.p. 24l-243C. Prepared by lithium aluminum hydride reduction of a-amino-3,4-dibenzyloxyphenylacetonitrile.

30. l-(3-Chlorphenyl)ethylenediamine dihydrochloride, m.p. 255270C. Prepared by lithium aluminum hydride reduction of a-amino-3- chlorophenylacetamide.

C. Preparation of 4-Substituted-2-Methylthio-Z-Imidazolines.

1. 2-Methylthio-4-(2-chlorophenyl)-2-imidazoline hydriodide.

An aqueous solution of l-(2-chlorophenyl)ethylenediamine dihydrochloride (51 g., 0.197 mole) is converted to the free base by treating with 50% sodium hydroxide. Isolation of the free base is carried out in the usual manner by extracting the basified solution with chloroform, drying the chloroform extract over potassium carbonate, and concentrating the dried solution under reduced pressure. Residual free base is taken up in 400 ml. of 80% ethanol and 12 ml. (15 g., 0.197 mole) of carbon disulfide is added in one portion. After stirring and refluxing the mixture for 1 hr., 1.5 ml. of concentrated hydrochloric acid is added and the mixture stirred for 10 hr. at reflux and then at room temperature for an additional 10 hr. period. The mixture filtered, washed with water, and dried provides 11.0 g. (73%) of 4-(2-chlorophenyl)-2-thio-2- imidazoline, m.p. 210-2l2C.

A solution of 4-(2-chlorophenyl)-2-thio-2- imidazoline (11.0 g., 0.052 mole) and 3.6 ml. (8.1 g., 0.057 mole) of methyl iodide in 75 ml. of isopropanol is refluxed for 3 hr. and the mixture concentrated in vacuo to approximately one-half volume. Dilution of the concentrated mixture with 1 liter of isopropyl ether provides 17.3 g., (94%) of product having a m.p. of l55l60C. Crystallization from absolute ethanolisopropyl ether provides analytically pure 2- methylthio-4-(2-chlorophenyl)-2-imidazoline hydriodide, m.p. l64-167C.

Analysis. Ca1cd.; C, 33.86; H, 3.41; N, 7.90. Found: C, 33.74; H, 3.40; N, 7.63.

Following the procedure described above for 2- methylthio-4-(2-chlorophenyl)-2-imidazoline but employing equimolar amounts of the following 1- phenylethylenediamines:

l-(4-chlorophenyl )ethylenediamine,

l-( 2,4-5-trimethylphenyl)ethylenediamine,

fl-benzylamino-4-chlorophenethylamine,

B-methylamino-4-chlorophenethylamine,

l-( 4-n-butoxyphenyl )ethylenediamine,

(4-biphenylyl)ethylenediamine, l-(4-isopropylphenyl )ethylenediamine, 1-(4-chlorobiphenylyl)ethylenediamine, 1-( 2,4,6-trichlorophenyl)ethylenediamine, 5 1-(3-methyl-4,6-dichlorophenyl)ethylenediamine,

l-phenylethylenediamine, in place of 1-(2-chlorophenyl)ethylenediamine there is produced:

2. 2-methylthio-4-(4-chlorophenyl)-2-imidazoline hydriodide,

3. 2-methylthio-4-(2,4,6-trimethylphenyl)-2- imidazoline hydriodide,

4. 2-methylthio-3-benzyl-4-(4-chlorophenyl)-2- imidazoline hydriodide,

5. 2-methylthio-3-methyl-4-(4-chlorophenyl)-2- imidazoline hydriodide,

6. 2-methylthio-4-(4-n-butoxyphenyl)-2-imidazoline hydriodide,

7. 2-methylthio-4-(4-biphenylyl)-2-imidazoline hydriodide,

8. 2-methylthio-4-(4-isopropylphenyl)-2-imidazoline hydriodide,

9. 2-methylthio-4-(4'-chloro-4-biphenylyl)-2- imidazoline hydriodide,

l0. 2-methylthio-4-(2,4,6-trichlorophenyl)-2- imidazoline hydriodide,

v1 1. 2-methylthio-4-(3-methyl-4,6-dichlorophenyl)-2- imidazoline hydriodide,

l2. 2-methy1thio-4-phenyl-2-imidazoline hydriodide, m.p. l96.5l98.5C. (corr.).

While several specific embodiments are disclosed in the foregoing specification, it will be appreciated by those skilled in the art that other modifications may be made without departing from the spirit and scope of the appended claims.

What is claimed is:

1. A method of producing a neuronal blocking and antihypertensive effect which comprises systemic administration to a mammal in need thereof a non-toxic effective dose of from about 0.1 to 50 mg./kg. body weight of said mammal to provide a neuronal blocking and antihypertensive effect of a compound selected from the group consisting of an imidazoline having the formula wherein when Y is said phenyl,

A is selected from the group consisting of henzylamino, halobenzylamino and 3- dimethylaminopropylamino; wherein when Y is said R-phenyl radical,

R is halogen, lower alkyl; benzyloxy, lower alkoxy,

lower dialkoxy, 3-hydroxy, 3,4-dihydroxy, trifluoromethyl, phenyl, 4-halophenyl, or 4-(lower alkyl)- phenyl with the proviso that when R is selected from the group consisting of halogen and lower alkyl the phenyl ring can have up to two additional substituents independently selected from the group consisting of halogen and lower alkyl; and is amino, hydroxyamino, lower alkylamino, benzylamino, halobenzylamino, dihalobenzylamino, allylamino, cycloalkylamino, hydrazino, halobenzylidenehydrazino, dihalobenzylidenehydrazino, or alkylidenehydrazino from 2 to 6 carbon atoms inclusive.

2. The process of claim 1 wherein said compound is 2-amino-4-(2-chlorophenyl)-2-imidazoline.

3. The process of claim 1 wherein said compound is 4-(2-chlorophenyl)-2-hydrazino-2-imidazoline.

4. The process of claim 1 wherein said compound is 4-( 2-chlorophenyl )-2-isopropylidenehydrazino-2- imidazoline.

5. The process of claim 1 wherein said compound is 2-amino-4-(4-chlorophenyl)-2-imidazoline.

6. The process of claim 1 wherein said compound is 2-amino-4-(4-chlorophenyl)-2-imidazoline hydrobromide. g i 7. The process of claim 1 wherein said compound is 2-amino-4-(4-bromophenyl)-2-imidazoline.

8. The process of claim 1 wherein said compound is 2-amino-4-(2,4-dichlorophenyl)-2-imidazoline.

9..The process of claim 1 wherein said compound is 2-amino-4-(2,6-dichlorophenyl )-2-imidazoline.

10. The process of claim 1 wherein said compound is 2-amino-4-(p-tolyl)-2-imidazoline.

11. The process of claim 1 wherein said compound is 2-amino-4-(4-biphenylyl)-2-imidazoline.

12. The process of claim 1 wherein said compound is 2-amin0-4-(3,4-dichlorophenyl)-2-imidazoline.

13. The process of claim 1 wherein said compound is 2-amino-4-(3,4-dichlorophenyl)-2-imidazoline hydrobromide.

14. The process of claim 1 wherein said compound is 2-amino-4-(m-tolyl)-2-imidazoline.

15. The process of claim 1 wherein said compound is 2-amino-4-[3 (benzyloxy)phenyl]-2-imidazoline.

16. The process of claim 1 wherein said compound 'is 2-amino-4-[3,4-dimethoxyphenyl]-2-imidazoline.

17. The process of claim 1 wherein said compound is 2-amino-4-(3-hydroxyphenyl)-2-imidazoline.

18. The process of claim 1 wherein said compound is 2-amino-4-( 3,4-dihydroxyphenyl)-2-imidazoline.

19. The process of claim 1 wherein said compound is 2-benzyl-amino-4-phenyl-2-imidazoline.

20. The process of claim 1 wherein said compound is 2-(4-chlorobenzylamino)-4-phenyl-2-imidazoline.

21. The process of claim 1 wherein said compound is 2-( 2,6-dichlorobenzylidenehydrazino )-4-( 2-chlorophenyl)-2-imidazoline.

22. The process of claim 1 wherein said compound is 4-( 4-chlorophenyl )-2-(methylamino )-2-imidazoline.

23. The process of claim 1 wherein said compound is 4-(4-chlorophenyl)-2-hydrazino-2-imidazoline. 

1. A METHOD OF PRODUCING A NEURONAL BLOCKING AND ANTIHYPERTENSIVE EFFECT WHICH COMPRISES SYSTEMIC ADMINISTRATION TO A MAMMAL IN NEED THEREOF A NON-TOXIC EFFECTIVE DOSE OF FROM ABOUT 0.1 TO 50 MG/KG. BODY WEIGHT OF SAID MAMMAL TO PROVIDE A NEURONAL BLOCKING AND ANTIHYPERTENSIVE EFFECT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF AN IMIDAZOLINE HAVING THE FORMULA
 2. The process of claim 1 wherein said compound is 2-amino-4-(2-chlorophenyl)-2-imidazoline.
 3. The process of claim 1 wherein said compound is 4-(2-chlorophenyl)-2-hydrazino-2-imidazoline.
 4. The process of claim 1 wherein said compound is 4-(2-chlorophenyl)-2-isopropylidenehydrazino-2-imidazoline.
 5. The process of claim 1 wherein said compound is 2-amino-4-(4-chlorophenyl)-2-imidazoline.
 6. The process of claim 1 wherein said compound is 2-amino-4-(4-chlorophenyl)-2-imidazoline hydrobromide.
 7. The process of claim 1 wherein said compound is 2-amino-4-(4-bromophenyl)-2-imidazoline.
 8. The process of claim 1 wherein said compound is 2-amino-4-(2, 4-dichlorophenyl)-2-imidazoline.
 9. The process of claim 1 wherein said compound is 2-amino-4-(2, 6-dichlorophenyl)-2-imidazoline.
 10. The process of claim 1 wherein said compound is 2-amino-4-(p-tolyl)-2-imidazoline.
 11. The process of claim 1 wherein said compound is 2-amino-4-(4-biphenylyl)-2-imidazoline.
 12. The process of claim 1 wherein said compound is 2-amino-4-(3,4-dichlorophenyl)-2-imidazoline.
 13. The process of claim 1 wherein said compound is 2-amino-4-(3,4-dichlorophenyl)-2-imidazoline hydrobromide.
 14. The process of claim 1 wherein said compound is 2-amino-4-(m-tolyl)-2-imidazoline.
 15. The process of claim 1 wherein said compound is 2-amino-4-(3-(benzyloxy)phenyl)-2-imidazoline.
 16. The process of claim 1 wherein said compound is 2-amino-4-(3,4-dimethoxyphenyl)-2-imidazoline.
 17. The process of claim 1 wherein said compound is 2-amino-4-(3-hydroxyphenyl)-2-imidazoline.
 18. The process of claim 1 wherein said compound is 2-amino-4-(3,4-dihydroxyphenyl)-2-imidazoline.
 19. The process of claim 1 wherein said compound is 2-benzyl-amino-4-phenyl-2-imidazoline.
 20. The process of claim 1 wherein said compound is 2-(4-chlorobenzylamino)-4-phenyl-2-imidazoline.
 21. The process of claim 1 wherein said compound is 2-(2,6-dichlorobenzylidenehydrazino)-4-(2-chlorophenyl)-2-imidazoline.
 22. The process of claim 1 wherein said compound is 4-(4-chlorophenyl)-2-(methylamino)-2-imidazoline.
 23. The process of claim 1 wherein said compound is 4-(4-chlorophenyl)-2-hydrazino-2-imidazoline. 